Abstract

The secretion of insulin and glucagon from the pancreas and the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) from the gastrointestinal tract is essential for glucose homeostasis. Several novel treatment strategies for type 2 diabetes (T2D) mimic GLP-1 actions or inhibit incretin degradation (DPP4 inhibitors), but none is thus far aimed at increasing the secretion of endogenous incretins. In order to identify new potential therapeutic targets for treatment of T2D, we performed a meta-analysis of a GWAS and an exome-wide association study of circulating insulin, glucagon, GIP, and GLP-1 concentrations measured during an oral glucose tolerance test in up to 7,828 individuals. We identified 6 genome-wide significant functional loci associated with plasma incretin concentrations in or near the SLC5A1 (encoding SGLT1), GIPR, ABO, GLP2R, F13A1, and HOXD1 genes and studied the effect of these variants on mRNA expression in pancreatic islet and on metabolic phenotypes. Immunohistochemistry showed expression of GIPR, ABO, and HOXD1 in human enteroendocrine cells and expression of ABO in pancreatic islets, supporting a role in hormone secretion. This study thus provides candidate genes and insight into mechanisms by which secretion and breakdown of GIP and GLP-1 are regulated.

Guidelines:
The Editorial Board will only consider letters that we deem relevant and of interest to our readers. We
will not post data that have not been subjected to peer review, nor will we post letters that are
essentially a reiteration of another letter. All accepted letters will be posted on our website within
one week of acceptance. We reserve the right to edit any letter for length, content, and clarity.
Authors of all accepted letters will be asked to preview any changes. Authors will be notified by e-mail
if their letters were not accepted. As this is a final decision, no appeals will be considered.

Specific requirements: All letters must be 400 words or fewer. You may enter the letter as plain
text or HTML. The author's name and e-mail address are required, and will be posted with the letter. All
possible conflicts of interest must be noted, even if they are not posted. If you wish to include a
figure (keep in mind that non-peer-reviewed data will not be posted), please contact the editors
directly at editors@the-jci.org.

First nameThis field is required

Last nameThis field is required

PositionThis field is required

InstitutionThis field is required

Email addressThis field is required

Other authors (Enter the list of colleagues in the following form: Stephanie Fulton, Thomas L. Wilding, and Frances Groen.)